The present invention relates to use of alkylaryl polyether alcohol polymers as antioxidants to suppress certain oxidant chemical reactions that cause tissue injury and disease in mammals and plants.
Oxygen is life-giving to aerobic plants and animals who depend on it for energy metabolism. It can also be lethal to those same organisms when it is altered from its stable dioxygen (O.sub.2) state to any one of three partially reduced species: a) the one electron reduced form superoxide anion (O.sub.2.sup.-); b) the two electron reduced form hydrogen peroxide (H.sub.2 O.sub.2); or the deadly three electron reduced form hydroxyl radical (.multidot.OH). In biologic systems O.sub.2.sup.- and H.sub.2 O.sub.2 are metabolic byproducts of a host of enzymes (oxygenases) that use oxygen as a cofactor. H.sub.2 O.sub.2 is also produced from O.sub.2.sup.- by the enzymatic action of superoxide dismutases. However, .multidot.OH is generally produced only when O.sub.2.sup.- and H.sub.2 O.sub.2 interact with transitional ions of metals such as iron and copper in dangerous cyclical redox reactions:
______________________________________ O.sub.2.sup.- + Fe.sup.3+ Fe.sup.2+ + O.sub.2 H.sub.2 O.sub.2 + Fe.sup.2+ Fe.sup.3+ + .sup.. OH + .sup.- OH ______________________________________
The above reaction is termed the superoxide driven Fenton reaction. The Fenton reaction can also be initiated by other reducing substances such as ascorbate in the presence of ferric iron and H.sub.2 O.sub.2.
While O.sub.2.sup.- and H.sub.2 O.sub.2 are each toxic for biological systems, .multidot.OH (and its alternate hypothesized form the ferryl intermediate FeO.sup.2+) is a highly reactive species that can oxidize unsaturated membrane lipids, damage cellular proteins and cause mutagenic strand breaks in DNA. To prevent injury from partially reduced O.sub.2 species under normal conditions, cells have evolved an elaborate system of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and antioxidant molecules (glutathione, alpha-tocopherol, beta carotene). However, when production of partially reduced O.sub.2 species exceeds the capacity of cellular antioxidant defenses to contain them, oxidant injury occurs. A growing number of mammalian disease entities are now thought to be related to overproduction of partially reduced O.sub.2 species, including the reperfusion injury syndromes myocardial infarction and stroke, adult respiratory distress syndrome, oxygen toxicity of the lung, lung injury from asbestos, Parkinson's disease, thermal and solar burns of the skin, and injury to the gastrointestinal tract from nonsteroidal anti-inflammatory agents (see Table IV, page 60, Halliwell B and Gutteridge JMC. Methods in Enzymology (1990) 186:1-85). Also, studies suggest that airway cells in cystic fibrosis patients are at risk of oxidant-mediated injury. The reason is that the leukocyte-derived enzyme, myeloperoxidase, present in large amounts in the bronchial secretions of cystic fibrosis patients, converts with H.sub.2 O.sub.2 produced by polymorphonuclear leukocytes to HOCl/OCl, the major leukocyte-derived oxidant. See, for instance, Cantin et al. "Protection by Antibiotics Against Myeloperoxidase-Dependent Cytotoxicity to Lung Epithelial Cells in Vitro," Journal of Clinical Investigation (January, 1993) 91:38-45; Ramsey et al., "Efficacy of Aerosolized Tobramycin in Patients with Cystic Fibrosis," The New England Journal of Medicine (June, 1993) 328:1740-1746; Vasconcellos et al., "Reduction In Viscosity of Cystic Fibrosis Sputum in Vitro by Gelsolin," Science (February, 1994) 263:969-971. Treatment of these conditions is increasingly directed either toward strategies that prevent enzymatic production of partially reduced O.sub.2 species and to the introduction of exogenous antioxidant compounds that restore oxidant-antioxidant balance in biologic and chemical systems.
Antioxidants are compounds that can be easily oxidized to stable chemical forms. They can protect chemical and biologic systems by sacrificing themselves to oxidation in preference to oxidation of critically important chemical and biologic molecules. Not all oxidizable compounds can perform an antioxidant function. To successfully protect chemical and biologic systems from oxidants, the antioxidant must have a higher reactivity for the oxidant than the chemical or biologic molecule which it seeks to protect. It is theoretically possible to synthesize a multitude of compounds with antioxidant properties. However, the factor limiting use of these antioxidants as treatments in biologic systems is the inherent toxicity of the antioxidant compounds themselves. Thus, it is a major advantage to discover that a class of commonly used and nontoxic ingredients in medicinal pharmacologic preparations are also potent antioxidants. Not only can such compounds react with partially reduced O.sub.2 species, but they can be used as treatments for oxidant mediated diseases without themselves causing toxicity to biologic systems.